DESCRIPTION: (condensed from applicants abstract): This grant focuses on defining the role of non-peptide containing primary afferents C fibers in nociception. Previous studies in the Basbaum lab have concentrated on the contribution of substance P-containing primary afferent C-fibers. However, the number of C fiber nociceptors that do not express peptides predominate yet we have little information concerning their phenotype, their neurocircuitry, or the type of pain provoked by their activation. While the peptide-containing afferents target laminae I and II outer, the non-peptidergic afferents target inner lamina II. The PI has demonstrated that these afferents express the vanilloid/capsaicin receptor and selectively express the 5HT-3 receptor. Thus, the PI will use activity at this receptor as a window into the contribution of the non-peptidergic population to nociceptive processing and pain. In a multi-faceted approach, anatomical, behavioral and electrophysiological studies in wild type and 5HT-3 receptor null mice will be used to address the function of these non-peptidergic afferents. Combined in situ and immunohistochemical studies will identify the neurochemical phenotype of the primary afferent neurons that express mRNA for the 5HT-3 receptor. In EM studies, the central termination of the non-peptidergic afferents will be investigated. In behavioral and anatomical studies, the PI will test the hypothesis that projection neurons in lamina I transmit the pain messages signaled by nociceptive activity in non-peptidergic afferents. In electrophysiological studies in the mouse, the PI will test the hypothesis that activity at the spinal 5HT-3 receptor facilitates the transmission of nociceptive messages. The results of these studies will provide new insights into the factors that contribute to the development of acute and persistent pain.